CN113521281B - Photothermal-photodynamic radiosensitization tumor treatment liquid gold microspheres and preparation method thereof - Google Patents
Photothermal-photodynamic radiosensitization tumor treatment liquid gold microspheres and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a liquid metal microsphere with the synergistic effect of three tumor treatment modes of photo-thermal treatment, photodynamic treatment and radiosensitization and a preparation method thereof. Firstly, connecting metronidazole MN to a polyethylene glycol-polyacrylic acid PEG-PAA copolymer chain by esterification reaction to prepare radiosensitization copolymer PEG-PAA-MN; then, preparing a copolymer RGD-PEG-PAA-MN of the targeted tumor by Michael addition reaction; gallium-based liquid metal is crushed into nano microspheres (LM) by an ultrasonic method, and then targeted copolymer RGD-PEG-PAA-MN is used for electrostatic coating on the surface of the LM to prepare the liquid metal nano composite microspheres. The method has the advantages of simple process, mild reaction conditions and easy operation; the prepared product has three functions of photo-thermal, composite photodynamic and hypoxic low-intensity radiosensitization for the cooperative treatment of tumors, and also has multiple tumor targeting properties, good biocompatibility, in-vivo degradability, tumor hypoxia response and acidic response performance.
Description
Technical Field
The invention relates to the technical field of nano materials, in particular to a targeted tumor copolymer coated liquid metal nano microsphere with the synergistic effect of three treatment modes of photo-thermal, photodynamic and radiosensitization and a preparation method thereof.
Background
Liver cancer is a malignant tumor which is primarily generated in liver cells or epithelial cells of intrahepatic bile ducts, and is the lethal cause of 5 th cancer and 2 nd cancer of new cases in China at present. Early symptoms of liver cancer are not obvious and the onset is hidden, so liver cancer patients are often diagnosed at a late stage; the optimal treatment period is lost, which brings great difficulty to the treatment. Even if effective treatment is given in the early stage of liver cancer, the recurrence rate is high, and particularly for patients with advanced cancer, the prognosis is not optimistic. Because the tumor has high infiltration, liver cancer can also spread to peripheral lymph nodes, resulting in a 5-year survival rate of only 11% for patients; when spread to other organs, its 5-year survival rate is only 3%.
Currently, methods for treating liver cancer include traditional surgical resection, liver transplantation, radiotherapy and chemotherapy; there are new therapeutic methods such as photothermal therapy and photodynamic therapy. Hepatectomy and liver transplantation are currently the most important means for obtaining long-term survival of liver cancer patients. However, after simple surgical resection, the probability of liver cancer recurrence is very high; the recurrence and transfer rate of the Chinese medicinal composition in 5 years is up to 40-70 percent; liver transplantation makes it difficult to find the corresponding liver. Chemotherapy can only delay the deterioration of tumors, thereby prolonging the survival time of patients, but simultaneously brings great pain to the patients. Radiotherapy is one of the effective and important methods for tumor therapy, and is a treatment measure adopted in clinical practice to avoid tumor recurrence and prolong the life of patients. The effectiveness of radiation therapy depends on the sensitivity of the radiation and the degree of response of different tissue organs and various tumor tissues to changes in radiation exposure. Radiosensitivity is related to the proliferative cycle and pathological grade of tumor cells, i.e., cells with active proliferation are more sensitive than cells without proliferation. The higher the degree of cell differentiation, the lower the radiosensitivity and vice versa. Furthermore, the oxygen content of tumor cells directly affects the sensitivity of tumors to radiation intensity.
The photothermal therapy of tumor is a therapeutic method that utilizes a photothermal agent (PTA) with high photothermal conversion efficiency to generate high thermal efficiency at the tumor under the irradiation of an external light source (generally near infrared light), thereby killing cancer cells and ablating the tumor. Photothermal therapy is a green physical therapy method, and has the advantages of wide application range, no wound, simple process, strong selectivity, small damage to normal tissues around the focus, and the like. The photodynamic therapy is that after being irradiated by light with certain wavelength, photosensitizer reacts with oxygen molecules and converts the oxygen molecules into active oxygen, and then tumor cells are destroyed by the effect of oxidative stress, so that the apoptosis of the cancer cells is induced. Currently, photodynamic technology has been applied to the treatment of clinical tumors.
In recent years, a low melting point room temperature Liquid Metal (LM) having good biocompatibility, photothermal conversion ability and changeability has been used in photothermal treatment of tumors. However, the treatment means is single, and the effect is not ideal. Therefore, combined multimodal treatment of cancer is currently the mainstream. The photothermal therapy has the advantages of minimal invasion, no toxic or side effect, short treatment time, obvious effect and the like, and has wide application in the field of tumor treatment; photodynamic therapy kills tumor cells or tissues from inside tumor tissues, can effectively and minimally invasively treat tumors, and is currently applied in clinic. Radiotherapy is one of the main means of tumor treatment in clinical application at present, and can inhibit the growth of local tumor. Therefore, the purpose of the patent is to construct a liquid metal composite nano microsphere with multiple functions for treating tumors. The system has good biocompatibility, biodegradability, tumor targeting, photothermal and photodynamic therapy and tumor hypoxia radiosensitization synergistic treatment effects.
The patent results (CN 110564157A; CN 111013503A; CN 102296405A) of the preparation of the composite liquid metal at home and abroad are searched, which shows that the method for preparing the liquid metal is only related at present, and the research and the report of the target polymer coated liquid metal nano microsphere for treating the tumor by photo-thermal, photodynamic and radiosensitization do not exist.
Disclosure of Invention
The invention aims to provide a preparation method of targeted composite liquid metal nano microspheres, which has the advantages of simple process, mild reaction conditions, easy operation, photo-thermal, photodynamic and radiosensitization cooperative tumor treatment functions, tumor targeting property, good biocompatibility, degradability, low-oxygen response and pH value response performance, and solves the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme:
on one hand, the invention provides a photothermal-photodynamic radiosensitization tumor treatment liquid gold microsphere, which is prepared by taking polyethylene glycol-polyacrylic copolymer PEG-PAA, 1-hydroxyethyl-2-methyl-5-nitroimidazole MN, arginine-glycine-aspartic acid short peptide RGD and liquid metal LM as raw materials through amidation reaction, Michael addition reaction and electrostatic coating.
The outer layer of the composite liquid metal microsphere is formed by connecting the PEG-PAA, the MN and short peptide RGD to a PEG and PAA molecular chain respectively through esterification reaction and Michael addition reaction, so that the obtained MN and RGD modified PAA-PEG copolymer molecular chain RGD-PAA-PEG-MN has targeting and ray sensitivity.
The inner layer of the composite liquid metal microsphere is the liquid metal nano microsphere at room temperature, and has the characteristics of photo-thermal property and photo-dynamic property; the composite liquid metal particle is characterized in that a PAA-PEG copolymer molecular chain modified by MN and RGD is coated on the surface of a liquid metal particle LM through electrostatic assembly, and hydrophilic short peptide RGD is arranged on the outermost surface of the composite particle, so that the composite liquid metal particle has targeting property; the composite liquid metal microsphere has a photo-thermal conversion effect and a photodynamic property under near infrared light irradiation, and has a photodynamic and ray sensitization property under radioactive irradiation, so that the composite liquid metal microsphere has a synergistic effect of photo-thermal, photodynamic and ray sensitization on tumors.
The preparation method of the photothermal photodynamic radiosensitization tumor treatment liquid gold microspheres is characterized by comprising the following steps:
a) adding 0.001-0.01 g of polyacrylic acid (PAA) with the molecular weight of 1000-20000 Da into 10-30 mL of 2- (N-morpholino) ethanesulfonic acid buffer (MES, 10Mm, pH 5.2); then adding 0.15-0.45 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) and 0.07-0.21 g of N-hydroxysuccinimide (NHS) into the solution to obtain a solution A; activating for 30min at room temperature to obtain a solution A, and adjusting the pH value of the solution A to 7.2 by using 300-900 mu L of Triethylamine (TEA) to obtain a solution B. Polyethylene glycol (Mal-PEG-NH) with a molecular weight of 1000-20000 Da and containing maleimide group at one end and amino group at the other end 2 0.2 to 0.6g) is added into the solution B; after reacting for 4-72 hours at room temperature, dialyzing by using a dialysis bag to remove unreacted substances in the solution; finally, freeze drying is carried out, thus obtaining the white PEG-PAA powder containing maleimide end groups.
b) Dissolving 0.05-0.15 g of PEG-PAA containing maleimide end groups in 5-15 mL of dimethyl sulfoxide (DMSO); then adding 0.041-0.123 g of EDC & HCl and 0.009-0.027 g of 4-Dimethylaminopyridine (DMAP) to the solution; after stirring and dissolving, adjusting the pH value of the solution to 7.2 by using 100-300 mu L of TEA to obtain a solution C, and reacting for 2 hours at room temperature; meanwhile, 0.01-0.08 g of 1-hydroxyethyl-2-methyl-5-nitroimidazole (MN) is dissolved in 1-6 mL of DMSO. Then, dropwise adding the MN solution into the solution C at the speed of 0.1-10 mL/min, and reacting for 4-72 hours at room temperature in a dark place; dialyzing the reaction solution for 3 days by using a dialysis bag with the cut-off molecular weight of 8000-14000 Da so as to remove unreacted substances; finally, freeze-drying to obtain white powder of MN modified PEG-PAA-MN.
c) Adding 0.01-0.03 g of PEG-PAA-MN into a nitrogen-filled dark three-neck flask, and adding 10-30 mL of PBS (pH 7.2) solution for dissolving; then adding 0.005-0.015 g of arginyl-glycyl-aspartic acid short peptide (RGD) marked by Fluorescein Isothiocyanate (FITC) into the solution to obtain a solution E, and reacting for 6-72 hours at room temperature in a dark place; finally, the yellow block copolymer powder RGD-PEG-PAA-MN modified by RGD and MN connection is obtained by dialysis and freeze drying.
d) Dissolving 0.01-0.03 g RGD-PEG-PAA-MN in 12-36 mL of mixed solution (absolute ethyl alcohol/water is 2-20: 1, v/v); and adding 0.2-0.6 g of liquid metal LM into the mixed liquid metal suspension to obtain a mixed liquid metal suspension F. Performing ultrasonic treatment for 1-10 hours in ice bath with the power of 100-1000W, then performing electrostatic assembly and coating on the surface of the metal microsphere for 0.1-1.0 hour by using a copolymerization molecular chain, and centrifuging at the rotating speed of 500-5000 rpm to remove large-size liquid metal particles; and finally, dispersing the small-sized composite liquid metal microspheres in PBS for storage to obtain the RGD-PEG-PAA-MN molecular chain electrostatically coated composite liquid metal microspheres RGD-PEG-PAA-MN @ LM.
As a further scheme of the invention: in the step a), the molecular weight of PAA is 1000-20000 Da; the activation time of the solution A is 10-60 minutes; one end of the solution B is maleimide group MAL, and the other end is amino group NH 2 The molecular weight of the PEG of (1) is 1000-20000 Da; the reaction time of the solution B is 4-48 hours.
As a further scheme of the invention: in the step b), the pH value of the solution C is 7.1-7.8; the concentration of the 1-hydroxyethyl-2-methyl-5-nitroimidazole MN solution is 1-45 mg/mL, and the dropwise adding rate is 0.1-10 mL/min; after the dropwise addition, the mass ratio of the PEG-PAA containing maleimide end groups to the 1-hydroxyethyl-2-methyl-5-nitroimidazole MN in the solution D is 10-1: 1.
As a further scheme of the invention: in the step c), the mass ratio of PEG-PAA-MN to FITC labeled RGD is 10-1: 1; and the reaction time of the solution E in the conditions of introducing nitrogen and keeping out of light is 2-72 hours.
As a further scheme of the invention: in the step d), the dispersing agent of the liquid metal suspension F is a mixed solution of ethanol and water, and the volume ratio of the ethanol to the water is 2-20: 1; ultrasonic treatment is carried out on the liquid metal in ice water at the power of 100-1000W, and the treatment time is 1-10 hours.
As a further scheme of the invention: in the step d), the liquid metal is any one of pure gallium, gallium indium alloy, gallium indium tin alloy and gallium indium tin zinc alloy.
As a further scheme of the invention: in the step d), in the RGD-PEG-PAA-MN mixed liquid metal suspension F, the mass ratio of the target modified copolymer RGD-PEG-PAA-MN to the metal liquid is 1: 5-50; after ultrasonic treatment, the RGD-PEG-PAA-MN molecular chain is assembled and coated on the surface of the metal liquid microsphere in a static way for 0.1 to 1.0 hour.
As a further scheme of the invention: the application of the photothermal photodynamic radiosensitization tumor treatment liquid gold microspheres is that the tumor which can be applied to multi-mode treatment comprises any one of osteosarcoma, brain glioma, ovarian tumor, melanoma, liver tumor, pancreas tumor and mastadenoma.
Compared with the prior art, the invention has the beneficial effects that:
the invention aims to provide a preparation method of the targeted composite liquid metal nanoparticle, which has the advantages of simple process, mild reaction conditions and easy operation, has the functions of photo-thermal conversion, composite photodynamic, hypoxic radiosensitization and cooperative tumor treatment under the irradiation of near infrared light or rays, and has the functions of multi-tumor targeting, good biocompatibility, in-vivo degradability, tumor hypoxic response and acidic response.
Drawings
FIG. 1 is a schematic diagram of the preparation and modification processes of a targeting polymer RGD-PEG-PAA-MN and a composite liquid metal nano-microsphere for tumor treatment.
FIG. 2 is the transmission electron microscope and scanning electron microscope photographs of the liquid metal nano-microsphere coated by the targeting copolymer.
FIG. 3 is a comparison graph of photothermal conversion before and after coating of liquid metal microspheres with tumor therapy copolymer chains at different concentrations.
FIG. 4 is a graph comparing the intensity of active oxygen generated by different materials and liquid metal microspheres under near infrared NIR and X-ray irradiation (photodynamic effect)
FIG. 5 is a graph comparing the cytotoxicity of liquid metal microspheres at different concentrations in hypoxic environment for liver tumor cells under different irradiation conditions.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in further detail below. The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Continuously improved nanotechnology has been applied in the field of cancer therapy, allowing to restore the unfavorable physicochemical properties of bioactive molecules to the ideal state of the biopharmacological profile; improving the therapeutic effect of the tumor by overcoming the biological barrier of the hemangioma; enhancing the therapeutic efficacy of a therapeutic agent drug by its selective delivery to a tumor target region; the diagnostic function is achieved by combining multi-mode simultaneous and sequential therapy into a multifunctional nano-platform.
The polyethylene glycol-polyacrylic acid (PEG-PAA) has good biocompatibility, and the polyethylene glycol-polyacrylic acid copolymer with good biocompatibility and biodegradability is used for modifying the surface of the nanoparticles, so that the phagocytosis and the uptake of the nanoparticles by an in vivo reticuloendothelial system can be effectively reduced, and the effective removal of the nanoparticles and metabolites thereof can be promoted.
The liquid metal is a metal having liquid fluidity at room temperature, and it is easily lowered in melting point after being compounded with other metals. Gallium (Ga) -based liquid metals have metallic properties such as high thermal and electrical conductivity, as well as high fluidity, flexibility, low viscosity, and low toxicity. Gallium compounds also have anti-inflammatory, antibacterial, and immunosuppressive activities. The gallium-indium alloy (EGaIn, the mass ratio of 75% Ga to 25% In) has less toxicity, is non-volatile and has no radioactivity; its high chemical stability also ensures its low toxicity and high biocompatibility; EGaLnSn alloy has been clinically used as dental filling biomaterial, showing good biocompatibility of gallium-based liquid metal and potential for large-scale clinical application.
According to the invention, the polyethylene glycol-polyacrylic acid copolymer is adopted, so that the controlled release and in vivo circulation half-life of the polymer nanoparticles can be obviously improved; polyacrylic acid with excellent pH value responsiveness is adopted, so that the prepared composite liquid metal microsphere also has good acidic response; the 1-hydroxyethyl-2-methyl-5-nitroimidazole is used as the hypoxic cell radiosensitizer, so that the prepared composite liquid metal microsphere has good hypoxic reduction response and a ray sensitizing effect, the radiation amount absorbed by the tumor can be effectively increased, and the radiotherapy effect of the tumor is improved.
The results of searching domestic and foreign literature and patents on the synthesis of polyethylene glycol-polyacrylic acid-1-hydroxyethyl-2-methyl-5-nitroimidazole block polymers show that only polyethylene glycol-polyglutamic acid-metronidazole amphiphilic nanoparticles (CN106750273A) and polyethylene glycol-polyglutamic acid-g-metronidazole amphiphilic block polymer micelle nanoparticles are used as tumor radiotherapy sensitizers (CN106750273B and CN108774319A), block hydrogel of N-isopropyl acrylamide-methacrylic acid polyethylene glycol monomethylether ester (CN102659978A) and preparation of polyethylene glycol-polyacrylic acid-metronidazole coated adriamycin microspheres (CN 2020101825223).
The liquid metal-coated RGD-PEG-PAA-MN composite microsphere is obtained by compounding the liquid metal microsphere and an RGD-PEG-PAA-MN copolymer chain. Wherein, the outer layer structure (RGD-PAA-PEG structure) of the nano-microsphere is used as a targeted protective barrier to separate the liquid metal microsphere from the organism, so as to avoid the toxic and side effects of the liquid metal to the organism tissue; when the RGD-PEG-PAA-MN coated liquid metal microspheres circulate in vivo and are gathered at tumor tissues through the targeting effect of RGD peptide; then the inner layer liquid metal structure of the composite microsphere can generate a large amount of oxygen free radicals under the irradiation of near infrared light and X rays so as to kill tumor cells; meanwhile, the liquid metal can also efficiently convert near infrared light into heat energy and can kill tumor cells; in addition, the 1-hydroxyethyl-2-methyl-5-nitroimidazole on the outer layer copolymerization chain can efficiently absorb X rays in the tumor anoxic environment to kill tumor cells; finally, under the acidic action in the tumor tissue environment, a large amount of metal ions can be slowly released, and the effect of tumor treatment can be achieved.
Therefore, the RGD peptide-polyethylene glycol-polyacrylic acid-1-hydroxyethyl-2-methyl-5-nitroimidazole copolymer molecular chain coated gallium-based liquid metal nano-microspheres synthesized by the Michael addition method and the electrostatic self-assembly coating method are applied to the sensitivity enhancement research of tumor radiotherapy and photothermal and photodynamic multi-mode combined treatment, and are not reported at present.
In order to make the person skilled in the art better understand the present invention, the drug-loaded microspheres with tumor radiotherapy and chemotherapy synergistic sensitization effect and the preparation method thereof are illustrated by a plurality of specific examples.
Example 1
0.01g of PAA with a molecular weight of 5000Da is added into a buffer (MES, 10Mm, pH 5.5) containing 10mL of 2- (N-morpholino) ethanesulfonic acid; 0.15g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) and 0.07g of N-hydroxysuccinimide (NHS) were added to the solution; after activation at room temperature for 30min, a mixed solution A was obtained, and the pH of the solution A was adjusted to 7.2 with 300. mu.L of Triethylamine (TEA) to obtain a solution B. Mixing polyethylene glycol (Mal-PEG-NH) with molecular weight of 5000Da and maleimide group at one end and amino group at the other end 2 0.2g) was added to solution B; after 48 hours of reaction at room temperature, the reaction solution was filled in a dialysis bag (MWCO: 7000) and dialyzed for 2 days to remove unreacted small molecules in the solution; and finally, freeze-drying the reaction product to obtain PEG-PAA white powder.
0.05g of PEG-PAA was dissolved in 5mL of DMSO; 0.041g of EDC. HCl and 0.009g of 4-Dimethylaminopyridine (DMAP) were added to the solution and dissolved; then, using 100 mu L of TEA to adjust the pH value of the solution to 7.2, and reacting for 2 hours at room temperature to obtain a solution C; 0.025g of 1-hydroxyethyl-2-methyl-5-nitroimidazole (MN) was dissolved in 2mL of DMSO. Adding the MN solution into the solution C dropwise at the speed of 2.0mL/min to obtain a solution D, and then stirring and reacting for 24 hours at room temperature in a dark place; and dialyzing the reaction solution in secondary water by using a dialysis bag with the molecular weight cutoff of 8000-14000 Da, and freeze-drying to obtain white powder of PEG-PAA-MN.
Adding 0.01g of PEG-PAA-MN into a three-neck flask which is filled with nitrogen and is protected from light; then 10mL of a PBS (pH 7.2) solution was added to dissolve PEG-PAA-MN; then adding 0.005g of RGD peptide with Fluorescein Isothiocyanate (FITC) mark into the solution to obtain solution E, and introducing nitrogen at room temperature to react for 24 hours in a dark place; then dialyzing in secondary water (MWCO: 8000-14000) for 2 days, and freeze-drying to obtain the RGD-PEG-PAA-MN yellow copolymer.
Dissolving 0.01g of RGD-PEG-PAA-MN in 12mL of mixed solution (volume ratio is 5:1) of ethanol and water; then adding 0.2g of gallium indium liquid alloy into the solution to obtain a liquid metal suspension F; ultrasonically treating the suspension in an ice water bath with 600W power for 4.5 hours, wherein the temperature of an ultrasonic pool is kept to be not higher than 4 ℃; then carrying out electrostatic assembly for 5min to ensure that the molecular chain of the copolymer is coated on the surface of the liquid metal microsphere; and then centrifuging at 1000rpm to remove large-size particles, and finally dispersing the supernatant in PBS for storage to prepare the RGD-PEG-PAA-MN @ LM composite microspheres.
Example 2
0.02g of PAA with a molecular weight of 6000Da is added into a buffer solution (MES, 10Mm, pH 5.5) containing 20mL of 2- (N-morpholino) ethanesulfonic acid; 0.30g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) and 0.14g of N-hydroxysuccinimide (NHS) are then added to the solution; after activation at room temperature for 30min, a mixed solution A was obtained, and then the pH of the solution A was adjusted to 7.2 with 600. mu.L of Triethylamine (TEA) to obtain a solution B. Mixing polyethylene glycol (Mal-PEG-NH) with molecular weight of 6000Da and maleimide group at one end and amino group at the other end 2 0.4g) was added to solution B; after 48 hours of reaction at room temperature, the reaction solution was filled in a dialysis bag (MWCO: 7000) and dialyzed for 3 days to remove unreacted small molecules in the solution; and finally, freeze-drying the reaction product to obtain PEG-PAA white powder.
0.10g of PEG-PAA was dissolved in 10mL of DMSO; then 0.082g of EDC & HCl and 0.018g of 4-Dimethylaminopyridine (DMAP) are added into the solution and stirred to dissolve; then, 200 mu L of TEA is used for adjusting the pH value of the solution to 7.2, and the solution is reacted for 2.5 hours at room temperature to obtain a solution C; 0.05g of 1-hydroxyethyl-2-methyl-5-nitroimidazole (MN) was dissolved in 4mL of DMSO. Adding the MN solution into the solution C dropwise at the speed of 1.0mL/min to obtain a solution D, and stirring and reacting for 24 hours at room temperature in a dark place; and dialyzing the reaction solution in secondary water for 3 days by using a dialysis bag with the molecular weight cutoff of 8000-14000 Da, and freeze-drying to obtain white powder of PEG-PAA-MN.
Adding 0.02g of PEG-PAA-MN into a three-neck flask which is filled with nitrogen and protected from light; then 20mL of PBS (pH 7.2) solution was added to dissolve PEG-PAA-MN; then adding 0.01g of RGD peptide with Fluorescein Isothiocyanate (FITC) mark into the solution to obtain a solution E, and introducing nitrogen at room temperature to react for 24 hours in a dark place; then dialyzing in secondary water (MWCO: 8000-14000) for 2 days, and freeze-drying to obtain the RGD-PEG-PAA-MN yellow copolymer.
Dissolving 0.02g of RGD-PEG-PAA-MN in 24mL of mixed solution (volume ratio is 6:1) of ethanol and water; then adding 0.4g of gallium indium tin liquid alloy into the solution to obtain a liquid metal suspension F; ultrasonically treating the liquid metal suspension in an ice-water bath with 700W of power for 5.0 hours, wherein the temperature of an ultrasonic pool is kept to be not higher than 4 ℃; then carrying out electrostatic assembly for 20min to ensure that the molecular chain of the copolymer is coated on the surface of the liquid metal microsphere; and then centrifuging at the speed of 1500rpm to remove large-size particles, and finally dispersing the supernatant in PBS for storage to prepare the RGD-PEG-PAA-MN @ LM composite microspheres.
Example 3
0.03g of PAA with a molecular weight of 4500Da is added to a buffer solution containing 30mL of 2- (N-morpholino) ethanesulfonic acid (MES, 10Mm, pH 5.5); 0.45g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) and 0.21g of N-hydroxysuccinimide (NHS) are then added to the solution; after activation at room temperature for 30min, a mixed solution A was obtained, and then the pH of the solution A was adjusted to 7.2 with 900. mu.L of Triethylamine (TEA) to obtain a solution B. Adding polyethylene glycol (Mal-PEG-NH) with molecular weight of 4500Da and maleimide group at one end and amino group at the other end 2 0.4g) was added to solution B; after 48 hours of reaction at room temperature, the reaction solution was filled in a dialysis bag (MWCO: 7000) and dialyzed for 3 days to remove unreacted small molecules in the solution; and finally, freeze-drying the reaction product to obtain PEG-PAA white powder.
0.15g of PEG-PAA was dissolved in 15mL of DMSO; then, 0.123g of EDC. HCl and 0.027g of 4-Dimethylaminopyridine (DMAP) are added into the solution and stirred to dissolve; then, 300. mu.L of TEA was used to adjust the pH of the solution to 7.2, and the reaction was carried out at room temperature for 2.5 hours to obtain solution C; 0.075g of 1-hydroxyethyl-2-methyl-5-nitroimidazole (MN) is simultaneously dissolved in 6mL of DMSO. Dropwise adding the MN solution into the solution C at the speed of 2.0mL/min to obtain a solution D, and stirring and reacting for 24 hours at room temperature in a dark place; and dialyzing the reaction solution in secondary water for 3 days by using a dialysis bag with the molecular weight cutoff of 8000-14000 Da, and freeze-drying to obtain white powder of PEG-PAA-MN.
Adding 0.03g of PEG-PAA-MN into a three-neck flask which is filled with nitrogen and is protected from light; then 30mL of a PBS (pH 7.2) solution was added to dissolve PEG-PAA-MN; then adding 0.015g of RGD peptide with Fluorescein Isothiocyanate (FITC) marks into the solution to obtain a solution E, and introducing nitrogen at room temperature to react for 24 hours in a dark place; then dialyzing in secondary water (MWCO: 8000-14000) for 2 days, and freeze-drying to obtain the RGD-PEG-PAA-MN yellow copolymer.
Dissolving 0.03g of RGD-PEG-PAA-MN in 36mL of mixed solution (volume ratio is 5:1) of ethanol and water; then adding 0.2g of gallium indium tin zinc liquid alloy into the solution to obtain a liquid metal suspension F; ultrasonically treating the suspension in an ice-water bath with 650W of power for 4 hours, wherein the temperature of an ultrasonic pool is kept to be not higher than 4 ℃; then, carrying out electrostatic assembly for 10min to ensure that the molecular chain of the copolymer is coated on the surface of the liquid metal microsphere; then centrifuging at 1000rpm to remove large-size particles, and finally dispersing the supernatant in PBS for storage to prepare the RGD-PEG-PAA-MN @ LM composite microspheres.
FIG. 1 is a reaction schematic diagram of preparation of polymer RGD-PEG-PAA-MN and targeting composite liquid metal nano microsphere RGD-PEG-PAA-MN @ LM. The figure shows that the method has the advantages of simple process, mild reaction condition, easy operation and the like.
FIG. 2 is a transmission electron microscope and a scanning electron microscope photo of the liquid metal nano microsphere RGD-PEG-PAA-MN @ LM coated by the targeting copolymer. As can be seen from the figure, the prepared RGD-PEG-PAA-MN @ LM composite liquid metal nano-microsphere is in a uniform spherical shape, the average particle size is 167nm, and the RGD-PEG-PAA-MN of the coating layer outside the LM can be seen in a transmission electron microscope picture.
FIG. 3 is a comparison graph of photo-thermal conversion before and after coating of liquid metal microspheres with different concentrations by targeting copolymer molecular chains. From the figure, it can be seen that the liquid metal microspheres before and after the copolymerization molecular chain coating increase the temperature of the dispersion liquid by more than 40 ℃ after the near infrared light irradiation, which indicates that the liquid metal microspheres have good photothermal conversion efficiency.
FIG. 4 is a graph comparing the intensity of active oxygen generated by different materials and liquid metal microspheres under near infrared NIR and X-ray irradiation (photodynamic effect). As can be seen from the figure, the liquid metal microspheres coated with the copolymer molecular chains have significantly enhanced photodynamic efficiency under the irradiation of near infrared rays and X-rays; compared with PBS, the active oxygen of the RGD-PEG-PAA-MN fractional system irradiated by near infrared light is increased by 26 times (shown in figure 4A), and the active oxygen of the RGD-PEG-PAA-MN dispersed system irradiated by X-ray is increased by more than 4 times.
FIG. 5 is a graph comparing the cytotoxicity of liquid metal microspheres against hypoxic liver tumor under different irradiation conditions. From the figure, as the concentration of the liquid metal nano microspheres increases, the toxicity of the tumor cells caused by the two liquid metal microspheres increases gradually as the concentration of the liquid metal nano microspheres increases; particularly, under the X-ray, the toxicity of the liquid metal microspheres coated by the copolymer molecular chain to the tumor cells is significantly greater than that of the liquid metal microspheres not coated by the copolymer molecular chain (shown in fig. 5B), and after the near-infrared and the X-ray are irradiated successively, the tumor cell toxicity of the RGD-PEG-PAA-MN @ LM is not only significantly greater than that of the LM, but also can completely kill the tumor cells at the concentration of 800mg/mL (shown in fig. 5C). Similar results are obtained from in vivo experiments in mice bearing tumor cells.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (6)
1. The photothermal photodynamic radiosensitization tumor treatment liquid gold microspheres are characterized in that the photothermal photodynamic radiosensitization tumor treatment liquid gold microspheres are prepared by taking polyethylene glycol-polyacrylic acid copolymer PEG-PAA, 1-hydroxyethyl-2-methyl-5-nitroimidazole MN, arginine-glycine-aspartic acid short peptide RGD and gallium-based liquid metal LM as raw materials through esterification reaction, Michael addition reaction and electrostatic assembly coating; the outer layer of the tumor treatment liquid metal microsphere is formed by respectively connecting the polyacrylic acid-polyethylene glycol copolymer PEG-PAA, the 1-hydroxyethyl-2-methyl-5-nitroimidazole MN and short peptide RGD to a PEG and PAA molecular chain through esterification reaction and Michael addition reaction, so as to obtain MN and RGD modified PAA-PEG copolymer molecular chain RGD-PAA-PEG-MN, which has tumor targeting and ray sensitivity enhancement; the inner layer of the liquid metal microsphere for treating tumor is a gallium-based liquid metal nano microsphere at room temperature, and has the characteristics of photo-thermal property and photo-dynamic property; the RGD-PAA-PEG-MN copolymer molecular chain modified by MN and RGD is coated on the surface of the liquid metal particle through electrostatic assembly, and the hydrophilic short peptide RGD is arranged on the outermost surface of the composite microsphere, so that the liquid metal particle for treating tumors has targeting property; the tumor treatment liquid metal microsphere has a photo-thermal conversion effect and a photodynamic property under near infrared light irradiation, and has a photodynamic and ray sensitization property under radioactive irradiation, so that the tumor treatment liquid metal microsphere has a synergistic effect of photo-thermal, photodynamic and ray sensitization on tumors.
2. A preparation method of a photothermal photodynamic radiosensitization tumor treatment liquid gold microsphere is characterized by comprising the following steps:
a) weighing 0.001-0.01 g of polyacrylic acid (PAA) with the molecular weight of 1000-20000 Da, and adding the polyacrylic acid (PAA) into 2- (N-morpholino) ethanesulfonic acid buffer (MES) with the concentration of 10-30 mL and the pH value of 5.2; then 0.15-0.45 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) and 0.07-0.21 g of N-hydroxysuccinimide (NHS) are added to the buffer; activating for 30min at room temperature to obtain a solution A, and adjusting the pH value of the solution A to 7.2 by using 300-900 mu L Triethylamine (TEA) to obtain a solution B; the molecular weight is 1000-20000 Da, one end contains maleimide group MAL, the other end contains amino group NH 2 0.2-0.6 g of polyethylene glycol (Mal-PEG-NH) 2 ) Adding the mixture into the solution B; after reacting for 48 hours at room temperature, dialyzing by using a dialysis bag to remove unreacted substances in the solution; finally, freeze drying to obtain white PEG-PAA powder containing maleimide end groups;
b) dissolving 0.05-0.15 g of PEG-PAA containing maleimide end groups in 5-15 mL of dimethyl sulfoxide (DMSO); then adding 0.041-0.123 g of EDC & HCl and 0.009-0.027 g of 4-Dimethylaminopyridine (DMAP) to the solution; after stirring and dissolving, adjusting the pH value of the solution to 7.2 by using 100-300 mu L of TEA to obtain a solution C, and reacting for 2 hours at room temperature; simultaneously dissolving 0.01-0.08 g of 1-hydroxyethyl-2-methyl-5-nitroimidazole (MN) in 1-6 mL of DMSO; then, dropwise adding the MN solution into the solution C at the speed of 0.1-10 mL/min to obtain a solution D, and reacting for 24 hours at room temperature in a dark place; dialyzing the reaction solution for 3 days by using a dialysis bag with the cut-off molecular weight of 8000-14000 Da so as to remove unreacted substances; finally, freeze-drying to obtain white powder of MN modified PEG-PAA-MN;
c) adding 0.01-0.03 g of PEG-PAA-MN into a dark three-neck flask filled with nitrogen, and adding 10-30 mL of PBS solution with the pH value of 7.2 for dissolving; then adding 0.005-0.015 g of arginyl-glycyl-aspartic acid short peptide (RGD) marked by Fluorescein Isothiocyanate (FITC) into the solution to obtain a solution E, and reacting for 2-72 hours at room temperature in a dark place; finally, the yellow block copolymer powder RGD-PEG-PAA-MN modified by the connection of RGD and MN obtained by dialysis and freeze drying;
d) dissolving 0.01-0.03 g of RGD-PEG-PAA-MN in 12-36 mL of a mixed solution of anhydrous ethanol and water in a volume ratio of 2-20: 1; adding 0.2-0.6 g of gallium-based liquid metal LM into the mixed liquid metal suspension to obtain a mixed liquid metal suspension F; performing ultrasonic treatment for 1-10 hours in ice bath with the power of 100-1000W, then performing electrostatic assembly and coating of a copolymerization molecular chain on the surface of the gallium-based liquid metal microsphere for 0.1-1.0 hour, and centrifuging at the rotating speed of 500-5000 rpm to remove large-size liquid metal particles; and finally dispersing the small-sized composite liquid metal microspheres in PBS for storage to obtain the RGD-PEG-PAA-MN @ LM of the composite liquid metal microspheres coated with the RGD-PEG-PAA-MN molecular chain in an electrostatic manner.
3. The method for preparing the photothermal photodynamic radiosensitizing tumor treatment liquid gold microspheres according to claim 2, wherein in step b), the concentration of the 1-hydroxyethyl-2-methyl-5-nitroimidazole MN solution is 1-45 mg/mL; after the dropwise addition, the mass ratio of the PEG-PAA containing maleimide end groups to the 1-hydroxyethyl-2-methyl-5-nitroimidazole MN in the solution D is 10-1: 1.
4. The method for preparing the gold microspheres for tumor therapy with photothermal photodynamic radiosensitization of claim 2, wherein in step c), the mass ratio of PEG-PAA-MN to FITC labeled RGD is 10-1: 1.
5. The method for preparing the photothermal photodynamic radiosensitizing tumor treatment liquid gold microsphere according to claim 2, wherein in step d), the gallium-based liquid metal is any one of pure gallium metal, gallium-indium alloy, gallium-indium-tin alloy and gallium-indium-tin-zinc alloy.
6. The method for preparing the photothermal photodynamic radiosensitizing tumor treatment liquid gold microspheres according to claim 2, wherein in step d), the mass ratio of the target modified copolymer RGD-PEG-PAA-MN to the gallium-based metal liquid is 1: 5-50 in the RGD-PEG-PAA-MN mixed liquid metal suspension F.
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